In the method of Dynamic Nuclear Polarization (DNP) the polarization of unpaired electron spins which in thermal equilibrium is much larger than that of nuclei having spin half or uneven multiples thereof is transferred by high frequency microwave irradiation to nuclear spins so as to enhance their NMR sensitivity. Only electron paramagnetic resonance (EPR)-active spins (unpaired electrons, also referred to as paramagnetic centers or radicals) are eligible for this polarization process. The electron spin system in DNP may be provided by an endogenous or exogenous paramagnetic polarizing agent. Most often in this technique a paramagnetic agent is added to the sample of interest.
Initially, compounds comprising one nitroxide radical or other g≈2 paramagnetic center were utilized as DNP agents for NMR applications. To improve DNP efficiency, the research groups of Robert Griffin and Timothy Swager from MIT introduced biradical polarizing agents consisting of two paramagnetic centers tethered together. For the last 7 years, the TOTAPOL biradical (U.S. Pat. No. 7,351,402 B2, WO 2008/048714, C. Song et al., J. Am. Chem. Soc., 2006, 128(35), 11385) has been the most widely used polarizing agent for biological applications due to its high solubility in aqueous solutions, high stability, and good DNP efficiency.
In 2008, the group of Robert Griffin and Timothy Swager disclosed 4,4-ureylene-di-(2,2,6,6-tetramethylpiperidinyloxyl) (“bis-TEMPO-urea” or “bTurea”) for use as a DNP agent (K. H. HU, C. Song, H. Yu, T. Swager, and R. Griffin J. Chem. Phys. 128, 052302 (2008)).
The present invention seeks to provide further dinitroxide compounds with improved DNP efficiency and/or solubility properties since the efficiency of polarizing agents for specific applications depend on a number of factors including the polarizing agent, analyte, solvent, and experimental conditions.